Ophthalmic formulation which modulates dilation

ABSTRACT

An ophthalmic formulation is disclosed which reduces dilation in dim light and reduces redness.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of earlier filed U.S. applicationSer. Nos. 09/705,526 filed Nov. 3, 2000; Ser. No. 09/675,988 filed Sep.29, 2000; Ser. No. 09/662,945 filed Sep. 15, 2000 now U.S. Pat. No.6,291,498 which claims priority to provisional patent applicationsSerial nos. 60/154,893 filed Sep. 20, 1999 and 60/154,033 filed Sep. 16,1999; and also claims priority to provisional 60/245,868 filed Nov. 3,2000 all of which are incorporated by reference and to which applicationclaims priority under Title 35 of the U.S.C. sections 120 and 119(e).

FIELD OF THE INVENTION

The present invention relates to a composition formulated andadministered to a human eye to reduce dilation and redness.

BACKGROUND OF THE INVENTION

While it is known that pupil size varies in its diameter in darknessbetween individuals from 3 mm to 9 mm, little attention has been paid tothe effect of this difference on the night vision and vision in dimlight (scotopic vision is dark adapted vision). Those with large pupilssuffer from much more light scatter, glare, halo, and related aberrantfocus of light rays that can make function under certain conditions oflighting very difficult.

Laser vision correction in particular has added new quality of visiondifficulties for many of these individuals. Exposing the retina to lightfocusing from as much as nine times more surface area essentiallymagnifies every variation in curvature from the ideal. Currently, onlydirect acting miotic agents such as pilocarpine are used in an effort todecrease pupil size.

Pilocarpine causes brow ache, ciliary muscle contraction and pseudomyopia, excessive dimness when first applied, and redness. Its effectlasts only a few hours, and it has known, though remote, risk of retinaldetachment probably related to pull on the retina from stimulatedciliary muscle contraction. For these reasons it is rarely tolerated orconsidered a clinically useful alternative for patients with largepupils in dim light.

Another medication used to affect pupil size is dapiprazole, an alpha-1adrenergic receptor blocking agent. Dapiprazole is5,6,7,8-tetrahydro-3-[2-(4-o,tolyl-1-piperazinyl)ethyl]-8-triazolo[4,3-a]pyridinehydrochloride. It is available in a 0.5% solution to partiallycounteract, or reverse, the dilation effect of phenylephrine, anadrenergic dilating agent, and the dilating and accommodation losscaused by tropicamide. In addition to producing redness uponinstillation, dapiprazole has very little effect on pupil size in dimlight in clinical application when used topically for this purpose, andtherefore its sole use is as a treatment of iatrogenically inducedmydriasis produced by adrenergic or parasympatholytic agents.

SUMMARY OF THE INVENTION

An ophthalmic formulation of the invention preferably obtains twosimultaneous effects (a) reducing the amount of dilation the eye wouldnormally undergo in a low light environment; and (b) reducing eyeredness. Reducing normal dilation can be obtained by administering acompound which interferes with the normal stimulation of muscles whichcause dilation. This can be done, for example, with an alpha 1antagonist. However, redness may be reduced using an alpha 1 agonist.The antagonist and agonist will, in general, counteract each other. Thepresent invention provides a particularly preferred formulation of (a)an alpha 1 antagonist which is phentolamine; and (b) an alpha 1 agonistwhich is tetrahydrozoline and specifically tetrahydrozoline hcl. Thiscombination reduces dilation and redness.

A formulation for optimizing pupil size in extreme lighting conditionsis disclosed. The formulation is preferably a solution of the type usedin an artificial tear formulation having dissolved therein atherapeutically effective amount of a compound characterized by itsability to reduce dilation of the eye, particularly in dim light. Thecompound generally interferes with a natural biochemical reaction whichresults in the stimulation of the dilator muscles of the eye. Theformulation is preferably further comprised of a compound which reduceseye redness, e.g. tetrahydrazolene. The compound which has the abilityto disrupt endogenous compounds which stimulate dilator muscles of theeye may be an alpha 1 antagonist which belongs to a class of compoundswith phentolamine or phenoxybenzamine groups.

A method of optimizing pupil diameter is disclosed wherein the pupildiameter in dim light is effected so that it is not more than 200%greater than its size in bright light. The method encompassesadministering a therapeutically effective amount of an alpha 1antagonist to an eye of a person in need thereof. The optimized pupildiameter in dim light may be no more than 5 mm, and the pupil diameterin bright light may be constricted no more than 1 mm. Further, theoptimized pupil diameter in dim light may be between and including 3 mmand 5 mm and will vary with different patients. Actual results withhuman patient's are shown in the Examples.

In accordance with the method of the invention an application devicesuch an eyedropper is utilized in order to apply a therapeuticallyeffective amount of an alpha 1 agonist to the eye of a patient which ispreferably the eye of a human patient. Thereafter, the formulation isallowed to effect the pupil of the eye and contract the pupil so thatthe pupil does not expand above a level which is twice the level ofdilation when the eye of the patient is present in bright light.Accordingly, another aspect of the invention is a formulation comprisedof an aqueous solution having an alpha 1 agonist present therein whereinthe formulation is present in an eyedropper.

The present invention is also directed to a method for optimizing pupildiameter in dim light by minimizing its dilatation in response to lesslight, comprising administering a therapeutically effective amount of analpha 1 antagonist to an eye of a person in need thereof. In thismethod, dilatation of the pupil diameter in dim light may be minimizedin response to less light compared with bright light, and the method maynot induce ciliary muscle contraction.

In the method of the present invention, the patient may suffer fromexcessively large pupils in dim light, and the patient may suffer frompoor quality of vision, and the patient may be undergoing medicationthat results in dilatation of the pupil diameter. Alternatively, thepupil diameter of the patient may be naturally excessively dilated as aresult of response to dimming of light.

The method of the invention may be carried out by directly instillingonto the eye an eye drop formulation of the invention. Optionally, thealpha 1 antagonist may be administered by contacting a contact lens, andthe contact lens applied to the eye. In the method of the invention, theused alpha 1 antagonist preferably may belong to a class of compoundsbelonging to the phentolamine or phenoxybenzamine groups.

The present invention is directed to a method for reducing pupildiameter in dim light in cases where dilation of the pupil is excessive,such as 6 mm or greater. Administering a formulation of the inventiondoes not induce ciliary contraction or undesirable pseudomyopia that mayresult from taking certain medication. Formulations disclosed herereverse mydriasis of parasympatholytic agents. Formulations of theinvention are effective on agents paralyzing accommodation such as 1%cylogyl, which can then be used for more complete cycloplegia andaccurate prelaser refractive measurement.

There are no generally available eye drops for optimizing pupil sizesuch as by reducing pupil diameter in dim light without undesirable sideeffects. The present invention recognizes that the alpha-1 antagonistswhich are currently used for treatment of high blood pressure, treatmentof pheochromocytoma, migraines, bladder spasm, prostate enlargement, andsexual dysfunction can be formulated used in reducing pupil diameter.

The present invention provides an ophthalmic. composition which achievesthe combined requirements of comfort and pupil diameter optimization.

Alpha adrenergic receptor antagonists function to block alpha-1 receptormediated contraction of arterial and venous smooth muscle. Alpha-2adrenergic receptors are involved in suppressing sympathetic output,increasing vagal tone, facilitating platelet aggregation, inhibiting therelease of norepinephrine and regulating metabolic effects. Alphaadrenergic antagonists have a wide spectrum of pharmacologicalspecificities and are chemically heterogeneous.

Alkylating agents, imidazolines, piperazinyl quinazolines and indolescomprise. the various chemical classes of alpha receptor antagonists.Many have both alpha-1 and alpha-2 receptor antagonist activity. For thepresent invention alpha-2 activity as represented by the indoles is ofno clinical benefit. The alkylating agents offer potential for long termeffectiveness for minimizing pupillary dilation, but are less effectiveand cause more redness than the imidazolines, such as phentolamine. Thepiperazinyl quinazolines, such as prazosin and dapiprazole, have amodest effect on pupil diameter in dim light, but to date our researchshows they are not as clinically effective as the imidazolines for thispurpose. Development of longer lasting, more potent piperazinylquinazolines may be clinically effective however. As phentolamine is notas strong an alpha-1 receptor antagonist as prazosin its strongerclinical benefit may relate to other related properties of the drug aswell as its alpha-1 antagonism. These properties include blockingreceptors for 5-HT, release of histamine from mast cells, and blockageof K+ channels. Phenoxybenzamine is similar in its chemical mediation.

An aspect of the invention is an ophthalmic formulation comprised of anaqueous solvent and an alpha 1 antagonist. The aqueous solvent may, inits simplest form, be water but is preferably a solvent comprised of anophthalmic artificial tear solution. The alpha 1 antagonist ispreferably present in a relatively low concentration e.g. less than 1%concentration. For example, the alpha 1 antagonist may be present in anamount in the range of 0.01 milligram per cubic centimeter of aqueoussolvent to about 50 milligram per cubic centimeter of solvent. Anotheraspect of the invention is the formulation of the invention presentwithin an application device such as a conventional or improvedeyedropper of the type described herein.

An advantage of the invention is that it can be utilized to treatpatients who have been subjected to laser surgery and have developed arange of different vision problems as a result of excessive dilation oftheir pupils.

A feature of the invention is that the alpha 1 antagonist can beformulated in a manner which is readily administered to the eye toobtain a desired effect.

These and other aspects, advantages and features of the invention willbecome apparent to those skilled in the art upon reading thisdisclosure.

DETAILED DESCRIPTION OF THE INVENTION

Before the present formulations and methods are described, it is to beunderstood that this invention is not limited to particular compounds,formulas or steps described, as such may, of course, vary. It is also tobe understood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyby the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges is also encompassed within the invention, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either both ofthose included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “acompound” includes a plurality of such compounds and reference to “thestep” includes reference to one or more step and equivalents thereofknown to those skilled in the art, and so forth.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

CHARACTERISTICS OF THE EYE

It is well known that pupillary dilation in dim light is a teleologicadaption to allow more light to enter our eyes. Along with adaptions onthe retina to scotopic, or night vision, this allows increased usefulacuity over a very large range of lighting in low lit situations. Lesswell known is the dramatic range that exists among human beings of thedegree to which pupils will dilate in dim light, ranging from maximaldilation in complete darkness of as little as 3 mm in some individualsto as high as 9 mm in others. This difference is part of the geneticmakeup of an individual.

When living in literal total darkness there may have been a very slightadvantage to having larger pupil diameters in dim light, but whateveradvantage was conferred has been lost once several advances incivilization resulted in illumination; including artificial means ofbackground lighting, neon lights. to allow signs to be more easily read,fluorescent light with its weighted blue more highly scatteringcomponent, and point sources of light caused by car headlights andtraffic lights. These light sources are visible at optimal quality whensufficient corneal diameter exists to allow light to enter, such as a 3mm pupil, but less corneal diameter is used to refract light, as lesslight scatter is induced than 5-6 millimeters pupils or larger. Thepreferred optimized pupil size in dim light according to the presentinvention is about 3-5 millimeters, more preferably 4-5 millimeters.

The peripheral corneal curvature in many people is not in perfectcurvature alignment with that of the central cornea. In individuals withsmall to moderate pupils in dim light the pupil acts as a filter so thatthe peripheral cornea in these cases is not a factor. But, for largerpupils in dim light, peripheral corneas may be either too steep or tooflat in many cases relative to the central curvature, causing sphericalaberration. These corneas are technically referred to as either prolateor oblate when imperfect. The eye drops of the present inventionclinically eliminate virtually all such spherical aberration, as theperipheral corneal curvature outside of a central 4-5 mm optical zoneare filtered by the treated smaller pupil in dim light and theextraneous light focused by the spherical aberration is eliminated.

Three millimeter pupils are sufficiently large to allow sufficient lightto enter the eye in scotopic situations, yet provide excellent filtersto minimize light scatter of ambient artificial light and or pointsources of light. Nine millimeter pupils on the other hand, utilizingnine times more corneal surface area, induce considerable light scatterof point sources, neon lights, and fluorescent blue light. While thecurrent state of the art within the ophthalmic and optometricprofessions does not generally recognize this distinction, and whereinrefractive surgery standard of care does not generally recognize adistinction in pupil diameter in, dim light as a predictive factor inoutcome, use of the novel pharmacologic method of the present inventionhas demonstrated this to be so in clinical use. Tables 1 and 2demonstrate the results of a study of several different alpha adrenergicantagonists on several patients, with different parameter beingmeasured.

Refractive optical aids such as glasses or contact lenses increase thedegree of light scatter in scotopic situations by adding opticalelements that are imperfect in that they have surfaces that scatterlight. Refractive surgery on the cornea, whereby a change in contour isinduced by surgical means that can include incision (RK), laser ablation(Lasik, PRK), or prosthesis (plastic segments inserted into the cornea)also adds imperfections that increase the degree of light scatter inscotopic conditions. The variables of pupil size in dim light andrefractive optics adding to light scatter has created circumstances inwhich individuals have quality of vision difficulty navigating inscotopic situations as a result of glare, halo, and related distortionsat night or in dimly lit environments of any kind.

The invention is particularly useful in treating patients who have beensubjected to various types of refractive surgery as described above.Because such surgery can increase the degree of light scatter theadministration of the formulation of the invention can modulate thiseffect by contracting the pupil. Thus, the invention includes carryingout refractive surgery on a patient and thereafter administering aformulation of the invention to the patient over time as needed e.g. tomaintain the pupil size at about 3-5mm, preferably 4-5mm. Theformulation of the invention may be administered periodically on a dailybasis (twice daily or as needed) and particularly administered insituations where the patient is subjected to dim light.

The term “dim light” is used herein to refer to a light environmentwherein the pupils of the patient are dilated to a substantially maximumamount. Alternatively, the term “bright light” is used herein todescribe a surrounding light environment wherein the pupil of thepatient's eye is contracted maximally i.e. dilated to a minimum amount.An aspect of the present invention is that the formulation can reducethe differential in pupil dilation and in particular reduce the dilationof the patient's pupil to an amount of 200% or less in dim light ascompared to the amount of dilation which would occur in bright light.

The method of the invention utilizes a novel pharmacologic means ofoptimizing pupil size by reducing pupil size in dim light. Conventionalteaching of eye specialists has been to use constricting agents of thepupil, such as acetylcholine or cholinesterase inhibitors to reducepupil size. Using dilute concentrations of such agents it is possible toconstrict the pupil and create improved viewing for affected individualsin scotopic environments. However, undesirable side effects of suchmedications, including excessive constriction initially causing severedimming, brow ache, generalized pain, redness, and induced blurringsecondary to ciliary accommodation, severely limits the value of theseclasses of pharmacologic agents. Retinal detachment is a known rarecomplication of its use.

PHARMACEUTICALLY ACTIVE COMPONENT

The pharmacologic method of the present invention utilizes a class ofcompounds known as alpha 1 antagonists to inhibit pupillary dilation inscotopic conditions preferentially over constriction of the pupil,affecting the dilator muscles of the iris preferentially, and has noclinically significant effect on the ciliary muscle responsible foraccommodation. This class of compounds has been used to treathypertension, prevent bladder spasmodic contractions and improve urinaryoutflow, and treat prostate enlargement. While toxic levels of alpha 1antagonists are known to cause pinpoint pupils, no formulation haspreviously been developed as a topical pharmaceutical agent to limitdilation of the iris.

A significant feature of the present invention is to employ more potentalpha antagonists, particularly alpha 1 antagonists, to allowimprovement in quality of vision in dim light without negative clinicaleffects in normal lighting conditions. Additionally, another feature ofthe present invention is to reverse the effects of parasympatholyticsmore effectively than dapiprazole.

The composition-of the present invention can be used to optimize pupilsize to obtain enhanced vision acuity in dim light by reducing the pupildiameter in dim light, but which does not clinically substantiallyreduce the pupil size in bright light, when the pupil size does notrequire it to be treated to reduce the pupil size to the same extent asthe pupil under dim light.

According to the invention, the optimized pupil diameter in dim light isno more than 200% greater than that in bright light. Preferably, thepupil diameter in dim light is no more than 150%, more preferably, 100%,even more preferably, 75%, still more preferably, 60%, still morepreferably, 50%, and most preferably, 33% greater than that in brightlight.

While the composition of the present invention can be used to optimizepupil size under any circumstances, the composition of the invention isadministered to the eye of an individual to reduce naturally occurringpupillary dilation in dim light, especially in situations where thedilation is excessive to affect vision acuity. The composition of theinvention can be used also to counteract pupil dilatation caused bymedication.

As used in the present application, alpha 1 antagonist refers to anyagent that binds to the alpha 1 adrenergic receptor, which includesalpha 1 adrenergic receptor antagonist. Preferably, the alpha 1adrenergic receptor is iris smooth muscle dilator selective. Morepreferably, the alpha 1 antagonist is in the phentolamine family, knownas imidazolines, an alkylating agent such as phenoxybenzamine, or apiperazinyl quinazoline with more potent alpha-1 adrenergic antagonistactivity than dapiprazole. Most preferably, the alpha 1 antagonist ofthe invention is phentolamine or phenoxybenzamine, but any alpha 1antagonist can be used in the present invention.

Alpha 1 antagonists such as phentolamine or phenoxybenzamine. Thesecompounds are currently used to treat pheochromocytoma, a condition inwhich alpha receptor stimulants such as epinephrine and norepinephrineare released throughout the body in extremely high concentration.

Examples of alpha 1 antagonist are disclosed within issued U.S. Pat. No.6,046,207 issued Apr. 4, 2000. Other examples are disclosed within U.S.Pat. Nos. 5,891,882 and 5,792,767. The above cited three U.S. patentsare incorporated herein by reference to disclose alpha 1 antagonist.Further, publications cited in these patents are incorporated herein byreference in order to disclose and describe therapeutically effectivecompounds which can be formulated and used in connection with thepresent invention when used in appropriate. ophthalmic formulations andapplied directly to the eye of a patient to effect pupil dilation.

FORMULATIONS—DOSAGE

According to the invention, an ophthalmic composition containing analpha 1 antagonist is advantageously applied topically to the eye,especially in the form of a solution, a suspension, an ointment, a gelor a solid insert. Such compositions comprise the active ingredient, forexample, in a range of from approximately 0.01 milligrams per cc toapproximately 50 milligrams per cc, preferably from approximately 0.05milligrams per cc to approximately 20 milligrams per cc, or morepreferably in the range of from approximately 0.1 milligrams per cc toapproximately 10 milligrams per cc and most preferably in the range offrom 1 milligram per cc to 5 milligrams per cc. The dose of the activeingredient may depend on various factors, such as mode ofadministration, requirement, age and/or individual condition.

A preferred concentration of 3.3 milligrams per cc is administered byplacing a single drop on a moist soft contact lens, and inserting thelens for 15-45 minutes, 1× per day. Administered in this manner the drophas a 20-24 hour clinical effectiveness, and in fact appears to havecumulative affect, such that with regular usage an every other dayadministration via the contact lens may be all that is necessary forsome patients. The contact lens dosing allows for preferentialabsorption within the cornea, maximizing drop utilization and minimizingmild redness that may otherwise occur as well as the remote risk ofsystemic absorption. The amount of phentolamine within 1 drop—less than0.33 mg—is about 15 × less than the clinically recommended dosing fortesting within the body. Of this it is unlikely as much as 10% wouldever reach the systemic circulation, resulting in 150× less than atypical clinical dosage. Using contact lens dosing this is estimated tobe'still 10× less, or 1500 times less than a typical clinical dosage.The drop may be administered in a 3.3 milligram per cc concentrationdirectly to the eye as a recommended daily or BID dosing.

An effective drop for the purpose of the present invention, because itlimits pupil dilation and does not significantly affect pupillaryconstriction should have significantly more effect and causesignificantly increased percentage reduction in pupil diameter inpatients with large pupils in dim light, whose dim light pupil exceedstheir daylight pupil considerably, and much less effect on pupildiameter in patients who have a more idealized pupil diameter in dimlight, where their dim light pupil is nearly equal to their daylightpupil. This is in fact the case with phentolamine as administered (seeTable 2).

There are used for a corresponding ophthalmic composition customarypharmaceutically acceptable excipients and additives known to the personskilled in the art, for example those of the type mentioned below,especially carriers, stabilizers, solubilizers, tonicity enhancingagents, buffer substances, preservatives, thickeners, complexing agentsand other excipients. Examples of such additives and excipients can befound in U.S. Pat. Nos. 5,891,913, 5,134,124 and 4,906,613. Suchcompositions are prepared in a manner known, for example by mixing theactive ingredient with the corresponding excipients and/or additives toform corresponding ophthalmic compositions. The active ingredient ispreferably administered in the form of eye drops, the active ingredientbeing conventionally dissolved, for example, in a carrier. The solutionis, where appropriate, adjusted and/or buffered to the desired pH and,where appropriate, a stabilizer, a solubilizer or a tonicity enhancingagent is added. Where appropriate, preservatives and/or other excipientsare added to an ophthalmic composition.

Carriers used in accordance to the present invention are typicallysuitable for topical or general administration, and are for examplewater, mixtures of water and water-miscible solvents, such as C₁- toC₇-alkanols, vegetable oils or mineral oils comprising from 0.5 to 5% byweight hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose,polyvinylpyrrolidone and other non-toxic water-soluble polymers forophthalmic uses, such as, for example, cellulose derivatives, such asmethylcellulose, alkali metal salts of carboxymethylcellulose,hydroxymethylcellulose, hydroxyethylcellulose,methylhydroxypropylcellulose and hydroxypropylcellulose, acrylates ormethacrylates, such as salts of polyacrylic acid or ethyl acrylate,polyacrylamides, natural products, such as gelatin, alginates, pectins,tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia,starch-derivatives, such as starch acetate and hydroxypropyl starch, andalso other synthetic products, such as polyvinyl alcohol,polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide,preferably cross-linked polyacrylic acid, such as neutral Carbopol, ormixtures of those polymers. Preferred carriers are water, cellulosederivatives, such as methylcellulose, alkali metal salts ofcarboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,methylhydroxypropylcellulose and hydroxypropylcellulose, neutralCarbopol, or mixtures thereof The concentration of the carrier is, forexample, from 1 to 100,000 times the concentration of the activeingredient.

The solubilizers used for an ophthalmic composition of the presentinvention are, for example, tyloxapol, fatty acid glycerol poly-loweralkylene glycol esters, fatty acid poly-lower alkylene glycol esters,polyethylene glycols, glycerol ethers vitamin E and vitamin Ederivatives, such as Vitamin E Tocopherol Polyethylene-.Glycol 1000Succinate (TPGS) or mixtures of those compounds. A specific example ofan especially preferred solubilizer is a reaction product of castor oiland ethylene oxide. Reaction products of castor oil and ethylene oxidehave proved to be particularly good solubilizers that are toleratedextremely well by the eye. Another preferred solubilizer is tyloxapol.The concentration used depends especially on the concentration of theactive ingredient. The amount added is typically sufficient tosolubilize the active ingredient. For example, the concentration of thesolubilizer is from 0.1 to 5000 times the concentration of the activeingredient.

According to the present invention lower alkylene means linear orbranched alkylene with up to and including 7 C-atoms. Examples aremethylene, ethylene, 1 ,3-propylene, 1,2-propylene, 1,5-pentylene,2,5-hexylene or 1,7-heptylene. Lower alkylene is preferably linear orbranched alkylene with up to and including 4 C-atoms.

Examples of buffer substances are acetate, ascorbate, borate, hydrogencarbonate/carbonate, citrate, gluconate, lactate, phosphate, propionate,perborate and TRIS (tromethamine) buffers. Tromethamine and boratebuffer are preferred buffers. The amount of buffer substance added is,for example, that necessary to ensure and maintain a physiologicallytolerable pH range. The pH range is typically in the range of from 5 to9, preferably from 6 to 8.2 and more preferably from 6.8 to 8.1.

Tonicity enhancing agents are, for example, ionic compounds, such asalkali metal or alkaline earth metal halides, such as, for example,CaCl₂, KBr, KCl, LiCl, Nal, NaBr or NaCl, or boric acid. Non-ionictonicity enhancing agents are, for example, urea, glycerol, sorbitol,mannitol, propylene glycol, or dextrose. For example, sufficienttonicity enhancing agent is added to impart to the ready-for-useophthalmic composition an osmolality of approximately from 50 to 1000mOsmol, preferred from 100 to 400 mOsmol, more preferred from 200 to 400mOsmol and even more preferred from 280 to 350 mOsmol.

Examples of preservatives are quaternary ammonium salts, such ascetrimide, benzalkonium chloride or benzoxonium chloride, alkyl-mercurysalts of thiosalicylic acid. such as, for example, thiomersal,phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate,parabens, such as, for example, methylparaben or propylparaben,alcohols, such as, for example, chlorobutanol, benzyl alcohol or phenylethanol, guanidine derivatives, such as, for example, chlorohexidine orpolyhexamethylene biguanide, or sorbic acid. Preferred preservatives arecetrimide, benzalkonium chloride, benzoxonium chloride and parabens.Where appropriate, a sufficient amount of preservative is added to theophthalmic composition to ensure protection against secondarycontaminations during use caused by bacteria and fungi.

The ophthalmic compositions may comprise further non-toxic excipients,such as, for example, emulsifiers, wetting-agents or fillers, such as,for example, the polyethylene glycols designated 200, 300, 400 and 600,or Carbowax designated 1000, 1500, 4000, 6000 and 10,000. Otherexcipients that may be used if desired are listed below but they are notintended to limit in any way the scope of the possible excipients. Theyare especially complexing agents, such as disodium-EDTA or EDTA,antioxidants, such as ascorbic acid, acetylcysteine, cysteine, sodiumhydrogen sulfite, butyl-hydroxyanisole, butyl-hydroxytoluene oralpha.-tocopherol acetate; stabilizers, such as a cyclodextrin,thiourea, thiosorbitol, sodium dioctyl sulfosuccinate ormonothioglycerol vitamin E and vitamin E derivatives, such as Vitamin ETocopherol Polyethylene Glycol 1000 Succinate (TPGS); or otherexcipients, such as, for example, lauric acid sorbitol ester, triethanolamine oleate or palmitic acid ester. Preferred excipients are complexingagents, such as disodium-EDTA and stabilizers, such as a cyclodextrin.The amount and type of excipient added is in accordance with theparticular requirements and is generally in the range of fromapproximately 0001 to approximately 90% by weight.

In another embodiment of the present invention, the ophthalmiccomposition comprises a therapeutically effective amount of alpha 1antagonist, a carrier, a solubilizer and another therapeuticallyeffective pharmaceutical agent which may be, for example, an antibiotic,an antiallergic, an anesthetic, or another drug.

A range of different alpha 1 antagonists are known to those skilled inthe art. The present invention is intended to encompass such compoundsand equivalent compounds which have substantially the same therapeuticeffect as the present invention. Specifically, the present invention isintended to encompass formulations which comprise an aqueous solventhaving dissolved therein a therapeutically effective amount of acompound which compound when dissolved in the formulation in a lowconcentration (1% or less) and administered to a human patient's eyewill prevent dilation of the eye in dim light to a level which is abouttwice the amount of dilation or less than occurs when the patient ispresent in bright light.

ARTIFICIAL TEARS

As indicated above a simple formulation of the present inventioncomprises an aqueous solvent which may be sterile water suitable foradministration to the eye having an alpha 1 antagonist dissolved thereinin a low concentration, e.g. 1% concentration or less. However,preferred formulations of the present invention are comprised of alpha 1antagonist dissolved in a formulation which is referred to in the art asan artificial tear formulation. Such formulations are disclosed anddescribed within U.S. Pat. No. 5,895,654; 5,627,611; and 5,591,426 aswell as patents and publications cited and referred to in these patents,all of which are intended to be incorporated herein by reference.

Artificial tear formulations of the invention promote good wettabilityand spread. Further, the artificial tear formulations preferably havegood retention and stability on the eye and do not cause significantdiscomfort to the user . A preferred artificial tear composition of theinvention, comprises

(1) polyvinylpyrrolidone, preferably in the amount of about 0.1-5% byweight of said solution;

(2) benzalkonium chloride, preferably in an amount of about 0.01-0.10%by weight;

(3) hydroxypropyl methylcellulose, preferably in an amount of about0.2-1.5% by weight of said solution; and

(4) glycerin, preferably in an amount of about 0.2-1.0% by weight ofsaid solution, wherein the composition is an aqueous solution havingisotonic properties.

Those skilled in the art will recognize that a wide range of differentformulations and artificial tear formulations which can be utilized inconnection with the present invention.

EYEDROPPERS

Formulations of the present invention can be administered in accordancewith means generally known to those skilled in the art. Generally, theformulation is administered using an eyedropper. The eyedropper may be aconventional eyedropper which is comprised of a hollow cylindricalbarrel having a first end and a second end and an inner surface.Further, the eyedropper will be further comprised of a means forproviding suction to draw the formulation of the invention into thehollow cylindrical barrel. The first end of the barrel is configured toreceive the means for providing suction to draw in a formulation. Thesecond end of the barrel is generally configured to have a small openingwhich permits passage of the formulation and allows drops of theformulation to be metered out directly onto the patient's eye. Thecylindrical barrel is preferably designed so that it is relatively smalland contains less than 5 cubic centimeters of formulation.

It may be desirable to utilize a measured dose eyedropper of the typedescribed within U.S. Pat. No. 5,514,118 or an illuminated eyedropperdevice of the type described in U.S. Pat. No. 5,584,823. A range ofother eye droppers can also be utilized of the type described within thefollowing U.S. Pat. No. 5,059,188; 4,834,727; 4,629,456; and 4,515,295.The patents cited here which disclose eyedroppers are incorporatedherein by reference as are the various patents and publications citedand discussed within these patents.

EXAMPLE 1

A 5 mg/ml vial of phentolamine was diluted in an artificial tearformulation to approximately 1.5 cc of solution. The artificial solutioncreated an effective composition for reducing the pupillary diameter indim light via topical instillation as an eye drop. This method inducesmild conjunctival and episcleral blood vessels causing very slightredness to the eye.

EXAMPLE 2

The composition of Example 1 is applied as a single drop to a moist softcontact lens with no excess saline, and the medication is deliveredtopically over an optional 15 minute to 2 hour period, 30 minutespreferred, through wear of the soft contact lens after which time it isremoved. This greatly reduces any systemic absorption of the medication,vasodilation of the vessels and minimizes redness as a result, whileallowing efficient drop utilization with the most effectiveconcentrations to reach the iris dilator muscles and minimize dilationin scotopic conditions. The loss of muscle tone of these muscles mayresult in very slight constriction of the pupil as well, but notsufficient to cause the dimness from a pinpoint pupil effect commonlyseen with acetylcholine or cholinesterase inhibitors. There is nonoticeable effect on accommodation.

Phenoxybenzamine has the advantage of creating a longer lasting alpha 1chemical sympathectomy, reducing the frequency of application requiredto maintain effective scotopic viewing.

Phentolamine as modified and applied requires a single instillation perday to render up to 20 to 24 hours of effect. Phenoxybenzamineformulations ranging from 0.1% to 5% have not been as effective asphentolamine, and induce much more vasodilation and congestion.Similarly, prazosin and tolamine at 0. 1% to .5% exhibits slightpupillary reduction in dilation in dim light but appears to be lesseffective than phentolamine. Labetalol, a potent beta adrenergicreceptor antagonist, consists of four isomers, two of which have somealpha-1 antagonist activity. Its S,S and S,R isomers, and inconcentrations of 0.1% to 2%, 0.5% preferred, are modestly effective.Other alpha-1 antagonists such as tamsulosin, bunazosin, alfuzonsin,urapidil, ketanserin, and indoramin, in concentrations of 0.1% to 2%,with 0.5% preferred are expected to have some clinical effectiveness aswell. Alpha-2 receptor antagonists, such as found in Yohimbe extract,have no effect on pupil dilation in dim light.

Neuroleptic agents such as chlorpromazine, and ergot alkaloids such asergotamine have mild alpha-1 receptor antagonist activity and mayexhibit mild effectiveness for the purposes of the present invention.

TABLE 1 Effect of Alpha Adrenergic Receptor Antagonists on PupilDilation Effect on Redness Adrenergic pupil diam. (direct receptors indarkness topical Duration Concen- Compound blocked (mm) instillation)(hrs) tration Phentolamine α-1 7.5 -> 4.0 + 20-40 3.3 mg/ml*Phenoxybenzamine α-1 7.5 -> 5.5 ++++ 20-?   5 mg/ml Prazosin α-1, 2 7.5-> 6 +++  5-12   5 mg/ml Dapiprazole α-1, 2 7.5 -> 7 +++  5-12   5 mg/mlYohimbe α-2 7.5 -> 7.5 +  0   5 mg/mI Tolamine α-1 7.5 -> 6 +  5-12   5mg/ml Labetalol α-1, β unknown unknown Not tested s,r, and s,s isomersonly alpha-1 antagonists Bunazosin α-1 unknown not avail Not tested USTamsulosin α-1 unknown not avail Not tested US *applied via soft contactlens with 1-2 gtts applied and placed for 30 minutes before removed

TABLE 2 Effect of Phentolamine 0.35% on Pupil Diameter** Dim Bright DimBright Light Light Light Light Sub- Pre Pre Post Post ject mm mm mm mmComment NF 7.0 3.5 4.0 3.0 Night vision good pre and post NB 7.5 4.0 4.03.0 Had glare, halos, poor night vision pre: post night = day = exc;glare = 0; halos 70% reduced; depth perception improved LR 7.5 3.0 4.02.5 Had glare, halo's poor night vision pre: post night much improved,dim light about same. GH 3.5 3.0 3.0 2.5 Night vision good pre and postLH 4.0 3.0 3.5 2.5 Night vision good pre and post **Phentolamine 3.3mg/cc applied as a single drop to a soft contact lens placed for 30minutes. Application of drops morning or daytime.

Whereas particular embodiments of this invention have been describedabove for purposes. of illustration, it will be evident to those personsskilled in the art that numerous variations of the details of thepresent invention may be made without departing from the invention asdefined in the appended claims.

All of the references cited herein are incorporated by reference intheir entirety.

What is claimed is:
 1. A method for controlling perceived light scattering, comprising: administering to a patient's eye an amount of a first compound sufficient to inhibit pupil dilation and thereby control light scattering perceived by the patient wherein the compound comprises an alpha-1-antagonist.
 2. The method of claim 1, wherein the perceived light scattering is due to corneal aberrations on the patient's eye.
 3. The method of claim 2, wherein the patient's corneal aberrations are a consequence of refractive eye surgery.
 4. The method of claim 2, wherein the patient's corneal aberrations are a consequence of natural irregularities of the eye.
 5. The method of claim 1, further comprising: administering a second compound to the patient's eye, wherein the second compound is characterized by its ability to reduce eye redness in the patient's eye while present with the first compound.
 6. The method of claim 5, wherein the second compound is a Tetrahydrozoline.
 7. The method of claim 6, wherein the second compound is Tetrahydrozoline HCl.
 8. A method for controlling perceived light scattering, comprising: administering to a patient's eye an amount of a first compound sufficient to inhibit pupil dilation and thereby control light scattering perceived by the patient wherein the compound comprises an imidazoline.
 9. The method of claim 8, wherein the imidazoline is selected from the group consisting of: Phentolamine and Tolamine.
 10. The method of claim 9, wherein the compound is Phentolamine.
 11. The method of claim 8, further comprising: administering a second compound to the patient's eye, wherein the second compound is characterized by its ability to reduce eye redness in the patient's eye while present with the first compound.
 12. The method of claim 11, wherein the second compound is a Tetrahydrozoline.
 13. The method of claim 12, wherein the second compound is Tetrahydrozoline HCl. 